Characterization of hitherto unknown Valsartan photodegradation impurities

A detailed investigation of Valsartan`s light-induced degradation is reported. Based on UPLC-HRMS studies of stressed solutions several degradation pathways are proposed. Some of the proposed structures were obtained by forced degradation experiments. Examination of analytical data including crystal structures allowed for structural revision of one literature-known degradant. In addition, irradiation under aerobic conditions revealed further degradative pathways leading to two previously unknown decomposition products. Mechanistic considerations regarding their origin helped to identify structural weak points of Valsartan under the influence of light

In situ preparation of a multifunctional chiral hybrid organic-inorganic catalyst for asymmetric multicomponent reactions

[EN] A chiral mesoporous organosilica material incorporating a urea based-cinchona derivative and propylamine groups was prepared by a co-condensation method. The multisite solid catalyst efficiently promoted the asymmetric multicomponent reaction of aldehydes, malonates and nitromethane.This work was supported by the Spanish Government (Consolider Ingenio 2010-MULTICAT (CSD2009-00050) and MAT2011-29020-C02-01). P.G.-G. is grateful for a JAE-DOC contract from CSIC co-funded by the ESF. The Severo Ochoa program is thankfully acknowledged.García García, P.; Zagdoun, A.; Coperet, C.; Lesage, A.; Díaz Morales, UM.; Corma Canós, A. (2013). In situ preparation of a multifunctional chiral hybrid organic-inorganic catalyst for asymmetric multicomponent reactions. Chemical Science. 4(5):2006-2012. https://doi.org/10.1039/C3SC22310HS2006201245José Climent, M., Corma, A., & Iborra, S. (2012). Homogeneous and heterogeneous catalysts for multicomponent reactions. 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Chemistry - A European Journal, 18(22), 6718-6723. doi:10.1002/chem.201200753Riente, P., Yadav, J., & Pericàs, M. A. (2012). A Click Strategy for the Immobilization of MacMillan Organocatalysts onto Polymers and Magnetic Nanoparticles. Organic Letters, 14(14), 3668-3671. doi:10.1021/ol301515dShi, J. Y., Wang, C. A., Li, Z. J., Wang, Q., Zhang, Y., & Wang, W. (2011). Heterogeneous Organocatalysis at Work: Functionalization of Hollow Periodic Mesoporous Organosilica Spheres with MacMillan Catalyst. Chemistry – A European Journal, 17(22), 6206-6213. doi:10.1002/chem.201100072Bleschke, C., Schmidt, J., Kundu, D. S., Blechert, S., & Thomas, A. (2011). A Chiral Microporous Polymer Network as Asymmetric Heterogeneous Organocatalyst. Advanced Synthesis & Catalysis, 353(17), 3101-3106. doi:10.1002/adsc.201100674Rueping, M., Sugiono, E., Steck, A., & Theissmann, T. (2010). Synthesis and Application of Polymer-Supported Chiral Brønsted Acid Organocatalysts. 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Enantioselective 1,3-Dipolar Cycloaddition of Cyclic Enones Catalyzed by Multifunctional Primary Amines: Beneficial Effects of Hydrogen Bonding. Angewandte Chemie International Edition, 46(40), 7667-7670. doi:10.1002/anie.200702618Díaz, U., García, T., Velty, A., & Corma, A. (2009). Hybrid organic–inorganic catalytic porous materials synthesized at neutral pH in absence of structural directing agents. Journal of Materials Chemistry, 19(33), 5970. doi:10.1039/b906821jLakshmi Kantam, M., & Sreekanth, P. (1999). Catalysis Letters, 57(4), 227-231. doi:10.1023/a:1019012019131Sartori, G. (2004). Catalytic activity of aminopropyl xerogels in the selective synthesis of (E)-nitrostyrenes from nitroalkanes and aromatic aldehydes. Journal of Catalysis, 222(2), 410-418. doi:10.1016/j.jcat.2003.11.016Wang, Q., & Shantz, D. F. (2010). Nitroaldol reactions catalyzed by amine-MCM-41 hybrids. Journal of Catalysis, 271(2), 170-177. doi:10.1016/j.jcat.2010.01.010Motokura, K., Tada, M., & Iwasawa, Y. 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Development of polymerizable BINOL derivatives for the creation of immobilized chiral Brønsted acids and ligands - Application in asymmetric catalysis

Im ersten Teil dieser Arbeit wurde die Entwicklung chiraler, katalytisch aktiver Polymere mit intrinsischer Mikroporosität vorgestellt. Zunächst wurden verschiedene enantiomerenreine BINOL-Derivate mit polymerisierbaren Substituenten synthetisiert. Nachfolgend erwies sich die oxidative Kupplung von Thiophenen als geeignete Polymerisationsmethode. Sie tolerierte alle benötigten funktionellen Gruppen und ermöglichte die Darstellung von Polymeren und Copolymeren aus Thienyl-substituierten Monomeren. Die hergestellten Feststoffe wiesen intrinsische Mikroporosität und hohe spezifische Oberflächen von bis zu 1247 m2 g-1 auf. Phosphorsäure-funktionalisierte Monomere und Polymere konnten anschließend erfolgreich als Organokatalysatoren in der enantioselektiven Transferhydrierung von Stickstoffhetero-cyclen eingesetzt werden. Strukturen, mit geringem Abstand zwischen den polymerisierbaren Gruppen und dem katalytisch aktiven Zentrum, zeigten nach der Polymerisation eine erhöhte Enantioselektivität von bis zu 60 % ee im Vergleich zu den entsprechenden monomeren Katalysatoren mit maximal 34 % ee. Demnach führte die Polymerisation sowohl zur Immobilisierung als auch zur Verbesserung der Enantioselektivität der monomeren Katalysatoren. Erste Untersuchungen zeigten, dass die heterogenen Katalysatoren einfach separiert und wiederverwendet werden können. Die Ergebnisse repräsentieren die ersten Beispiele für eine enantioselektive Organokatalyse mit mikroporösen organischen Polymeren. Im zweiten Teil dieser Arbeit wurde ein polymerisierbarer Octahydro-BINOL-Ligand hergestellt. Der Ligand ist den Monoalkoxy-Liganden in den neusten Schrock-Metathese-Katalysatoren nachempfunden und soll als Grundlage für Untersuchungen zur Immobilisierung dieser Katalysatoren dienen. Als polymerisierbare Gruppe wurde eine Norborneneinheit gewählt, die mit der Silylschutzgruppe im Liganden verknüpft wurde. Die Stabilität der Schutzgruppe wurde durch die Variation der übrigen Alkylsubstituenten am Silizium optimiert. Das entsprechende Silylchlorid wurde über eine Hydrosilylierung als Schlüsselschritt hergestellt und erfolgreich mit 3,3‘-Dibrom-Octahydro-BINOL umgesetzt. Die flexible Syntheseroute ermöglicht zudem einen einfachen Zugang zu weiteren Liganden mit unterschiedlicher Halogensubstitution, die im Rahmen dieser Arbeit nicht mehr hergestellt wurden.In the first part of this thesis chiral catalytically active polymers with intrinsic microporosity were presented. First, different enantiomerically pure BINOL derivatives were synthesized. Afterwards the oxidative coupling of thiophenes turned out to be an appropriate polymerization method. All required functional groups were tolerated and the creation of polymers and copolymers out of thienyl substituted monomers was possible. The produced solids were intrinsic microporous and showed specific surface areas of up to 1247 m2 g-1. Then Phosphoric acid functionalized monomers and polymers could be successfully used as organocatalysts in the enantioselective transfer hydrogenation of nitrogen heterocycles. Structures with little space between polymerizable groups and the catalytically active centre showed after polymerization increased enantioselectivity of up to 60 % ee in comparison to the corresponding monomeric catalyst with maximum 34 % ee. Thus polymerization led to immobilization as well as enhancement of enantioselectivity of the monomeric catalyst. First experiments showed that the heterogeneous catalysts can easily be separated and reused. These results represent the first examples of enantioselective organocatalysis with microporous organic polymers. In the second part of this thesis a polymerizable octahydro-BINOL ligand was presented. The ligand is patterned on the monoalkoxy ligand in the latest Schrock metathesis catalysts and should serve as a basis for investigation of the immobilization of these catalysts. A norbornene group was chosen as polymerizable group and was connected to a silyl protecting group. The stability of the protecting group was optimized by variation of the alkyl substituents on the silicon atom. The corresponding silyl chloride was synthesized via hydrosilylation as a key step and was then successfully reacted with 3,3‘-Dibrom-Octahydro-BINOL. Furthermore the flexible synthesis enables an easy access to further ligands with different halide substituents. This has not been accomplished anymore within this thesis

Direct Trapping of Sterically Encumbered Aluminum Enolates

The formation of chiral and sterically congested cyclohexanone derivatives has been achieved through a multistep sequence with one single purification step. (n-Butoxymethyl)-diethylamine was identified as a highly efficient reagent for the direct trapping of aluminum enolates. The Lewis acidic character of aluminum suffices to activate the α-aminoether to form in situ an electrophilic iminium species. In return the aluminum enolate is rendered more nucleophilic by coordination of the butoxy group and formation of an aluminate

Catalytic Enantioselective Total Synthesis of Riccardiphenol B

The first catalytic enantioselective total synthesis of riccardiphenol B, a sesquiterpene derivative isolated from a Japanese collection of the liverwort Riccardia crassa, has been achieved. A copper-catalyzed asymmetric conjugate addition of trimethylaluminum was used at an early stage to generate the quaternary stereogenic center with high enantiomeric excess. The corresponding sterically encumbered aluminum enolate was directly trapped with an α-amino ether, allowing after oxidation, the release of a key intermediate in the total synthesis of the target natural product

Direct Trapping of Sterically Encumbered Aluminum Enolates

The formation of chiral and sterically congested cyclohexanone derivatives has been achieved through a multistep sequence with one single purification step. (<i>n</i>-Butoxymethyl)-diethylamine was identified as a highly efficient reagent for the direct trapping of aluminum enolates. The Lewis acidic character of aluminum suffices to activate the α-aminoether to form <i>in situ</i> an electrophilic iminium species. In return the aluminum enolate is rendered more nucleophilic by coordination of the butoxy group and formation of an aluminate